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Predisposing factors for the development of diabetic ketoacidosis with lower than anticipated glucose levels in type 2 diabetes patients on SGLT2-inhibitors: a review.
Bamgboye, AO, Oni, IO, Collier, A
European journal of clinical pharmacology. 2021;(5):651-657
Abstract
PURPOSE SGLT2-inhibitors (SGLT-2i) have been linked to the risk of potential life-threatening diabetic ketoacidosis (DKA). The U.S. Food and Drug Administration and the European Medicines Agency issued warnings in 2015 and 2016 respectively on the predisposing factors to the development of DKA in individuals on an SGLT2i. New predisposing factors to DKA are still being discovered with the use of SGLT-2i. The list by FDA and EMA is yet to be updated. This article aims to provide a holistic list that includes the newer factors that have been implicated in the development of DKA. The overall aim is to guide physicians in prescribing this class of drugs for type 2 diabetes mellitus (T2D). METHOD A search was done using PUBMED, Google Scholar, and Directory of Open Access Journals with the following words: SGLT-2 Inhibitors AND Ketoacidosis were entered. We included articles from 2000 to 2020, those in English, those involving any of the approved SGLT2i medications in T2D patients, and studies that focused on DKA linked to SGLT-2i. These articles were reviewed, and relevant data extracted and compiled. RESULTS AND CONCLUSION The review has revealed that predisposing factors include (excess) alcohol consumption, female gender, starvation due to illness or fasting, withholding the use of SGLT2i for less than 48 h peri-operatively, and the existence of a variations in the expression of SGLT2 receptors. Patients should be advised on "sick day rules," and if a patient becomes unwell while on an SGLT2i, they should be advised to withhold the medication for the duration of the intercurrent illness.
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Fluid and electrolyte therapy in childhood diabetic ketoacidosis management: A rationale for new national guideline.
Agwu, JC, Ng, SM
Diabetic medicine : a journal of the British Diabetic Association. 2021;(8):e14595
Abstract
Fluid and electrolyte therapy in childhood diabetic ketoacidosis (DKA) management has been controversial. Previous National Institute for Health and Care Excellence (NICE) 2015 guidance advocated a restricted fluid regimen while more recent guidelines have advocated a more liberal approach to fluid replacement in DKA. At the core of the debate is the need to avoid developing cerebral oedema as a complication. Although subtle asymptomatic cerebral oedema is common in children presenting in DKA, clinically apparent cerebral oedema is rare and has been reported in approximately 0.5%-1% of DKA cases in children. Recent research evidence has shown that there was no clear evidence of a difference in rates of clinically apparent cerebral injury in children in DKA managed with a range of fluid volumes and rates of rehydration. In view of this, NICE has updated its guideline. In this paper, we review literature evidence underpinning the current understanding of the pathophysiology of cerebral oedema in children and discuss the rationale for the new NICE guidance.
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Is Age a Risk Factor for Cerebral Edema in Children With Diabetic Ketoacidosis? A Literature Review.
Glackin, S, Metzger, D, Hanas, R, Chanoine, JP
Canadian journal of diabetes. 2020;(1):111-118
Abstract
Cerebral edema (CE) is a rare but potentially fatal complication of diabetic ketoacidosis (DKA) in children with type 1 diabetes. CE is frequently mentioned as being more common in young children. The primary objective of this study was to review the evidence suggesting that younger age is a risk factor for the development of CE during DKA. The secondary objective was to assess if younger children are at a higher risk of DKA and severe DKA. A literature review was performed, and studies which reported the frequency of CE, DKA and severe DKA in children <3 and 3 to 5 years of age were included. Among the 6 studies reporting the frequency of CE that were identified, 5 good-quality studies found no significant association between younger age and higher risk of CE. Twenty-seven studies (DKA frequency: 11.3% to 54%) reported DKA frequency as a function of age. Most published studies found a higher frequency of DKA in children <5 years of age (20/25 studies), and in particular in those in the first 2 to 3 years of life (8/8 studies). There was inconclusive evidence to determine whether the severity of DKA was influenced by age. In conclusion, the commonly held view that CE is more common in younger children is not supported by the existing literature. Published data suggest that DKA (and possibly severe DKA) is more common in very young children. Regardless of age, all children with DKA should be monitored carefully for the development of CE.
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Steroid-Induced Diabetes Ketoacidosis in an Immune Thrombocytopenia Patient: A Case Report and Literature Review.
Alakkas, Z, Alzaedi, OA, Somannavar, SS, Alfaifi, A
The American journal of case reports. 2020;:e923372
Abstract
BACKGROUND Steroids are used as anti-inflammatory agents, administered for a variety of medical conditions, either as short- or long-term treatment. Steroid use is associated with many adverse effects, including hyperglycemia, but ketoacidosis is rare. CASE REPORT We present the case of a 53-year-old woman who developed diabetic ketoacidosis after administration of methylprednisolone during treatment of immune thrombocytopenic purpura. She did not have diabetes or a family history of diabetes. Steroid-induced hyperglycemia with insulin resistance, lipolysis, and ketogenesis occurred and were likely to have precipitated the ketoacidosis. Blood glucose, blood gases, and urine test results were diagnostic for ketoacidosis. CONCLUSIONS The risk of ketoacidosis and hyperglycemia should be considered in the course of steroid therapy, even without a diagnosis of diabetes, especially in patients who have risk factors for diabetes mellitus including obesity and long-term use of steroids, so that early identification of diabetic ketoacidosis can prevent further morbidity and mortality in chronic patients.
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Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease.
Milder, TY, Stocker, SL, Day, RO, Greenfield, JR
Drug safety. 2020;(12):1211-1221
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a major advance in the fields of diabetology, nephrology, and cardiology. The cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of their glycaemic effects, and this understanding is central to the use of these agents in the high-risk population of people with type 2 diabetes and chronic kidney disease. There are a number of potential safety issues associated with the use of SGLT2 inhibitors. These include the rare but serious risks of diabetic ketoacidosis and necrotising fasciitis of the perineum. The data regarding a possibly increased risk of lower limb amputation and fracture with SGLT2 inhibitor therapy are conflicting. This article aims to explore the potential safety issues associated with the use of SGLT2 inhibitors, with a particular focus on the safety of these drugs in people with type 2 diabetes and chronic kidney disease. We discuss strategies that clinicians can implement to minimise the risk of adverse effects including diabetic ketoacidosis and volume depletion. Risk mitigation strategies with respect to SGLT2 inhibitor-associated diabetic ketoacidosis are of particular importance during the current coronavirus disease 2019 (COVID-19) pandemic.
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Diabetic ketoacidosis precipitated by COVID-19: A report of two cases and review of literature.
Reddy, PK, Kuchay, MS, Mehta, Y, Mishra, SK
Diabetes & metabolic syndrome. 2020;(5):1459-1462
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BACKGROUND AND AIMS The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) and diabetes mellitus is bidirectional. On one hand, diabetes mellitus is associated with an increased risk of severe COVID-19. On the other hand, new onset diabetes and severe metabolic complications of pre-existing diabetes, including diabetic ketoacidosis (DKA) have been observed in patients with COVID-19. In this report, we describe two patient with diabetes mellitus who presented to our hospital with DKA. We also reviewed almost all published cases of DKA that had been precipitated by COVID-19. METHODS Two patients were admitted with DKA, who were diagnosed to have COVID-19 on the basis of real time reverse transcription-polymerase chain reaction (RT-PCR) assay. Detailed history, anthropometry, laboratory investigations, imaging studies, clinical course and management outcomes were documented. RESULTS First patient (30-year-male) had undiagnosed diabetes and no other comorbidities, and COVID-19 precipitated DKA. He also had COVID-19-associated pneumonia. Second patient (60-year-male) had long duration hypertension with no prior history of diabetes and developed cerebrovascular accident (CVA). He was also diagnosed with COVID-19 (RT-PCR assay) and DKA in the hospital. CVA and COVID-19 could have precipitated DKA. Both patients responded well to treatment and were discharged in a stable condition. CONCLUSIONS These cases show that COVID-19 can precipitate DKA in a significant number of patients. DKA can occur in patients with pre-existing diabetes or newly diagnosed diabetes. As COVID-19 and diabetes are prevalent conditions, high degree of suspicion is required to diagnose DKA timely in order to improve the prognosis of COVID-19-related diabetic ketoacidosis.
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SGLT2 inhibitors and metformin: Dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes.
Donnan, K, Segar, L
European journal of pharmacology. 2019;:23-29
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The prevalence of type 2 diabetes mellitus (T2D) has risen in the United States and worldwide, with an increase in global prevalence from 4.7% to 8.5% between 1980 and 2014. A variety of antidiabetic drugs are available with different mechanisms of action, and multiple drugs are often used concomitantly to improve glycemic control. One of the newest classes of oral antihyperglycemic agents is the sodium glucose cotransporter-2 (SGLT2) inhibitors or "flozins". Recent clinical guidelines have suggested the use of SGLT2 inhibitors as add-on therapy in patients for whom metformin alone does not achieve glycemic targets, or as initial dual therapy with metformin in patients who present with higher glycated hemoglobin (HbA1c) levels. The FDA has approved fixed-dose combination (FDC) tablets with each of the three available SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and metformin. Both drug classes are associated with the rare but serious life-threatening complications that result from metabolic acidosis, including lactic acidosis (with metformin) and euglycemic diabetic ketoacidosis (with SGLT2 inhibitors). This review summarizes the current literature on the pharmacokinetics and the molecular targets of metformin and SGLT2 inhibitors. It also addresses the common adverse effects and highlights the molecular mechanisms by which this dual antihyperglycemic therapy contributes to high anion gap metabolic acidosis. In conclusion, while the combination of metformin and SGLT2 inhibitors would be a better option in improving glycemic control with a low risk of hypoglycemia, an increase in the risk of metabolic acidosis during combination therapy may be borne in mind.
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Tacrolimus-induced diabetic ketoacidosis with subsequent rapid recovery of endogenous insulin secretion after cessation of tacrolimus: A case report with review of literature.
Maruyama, K, Chujo, D
Medicine. 2019;(36):e16992
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RATIONALE Immunosuppressive agents such as tacrolimus (TAC) and cyclosporin might cause glycemic disorders by suppressing insulin production. However, only a few cases of diabetic ketoacidosis (DKA) with longitudinal evaluation of endogenous insulin secretion related to TAC administration have been reported. PATIENT CONCERNS A 59-year-old Asian woman, who received prednisolone and TAC 4.0 mg for the treatment of anti-aminoacyl-tRNA synthetase antibody-positive interstitial pneumonia, was admitted to our hospital due to impaired consciousness and general malaise. DIAGNOSES She had metabolic acidosis; her plasma glucose, fasting serum C-peptide immunoreactivity (CPR), and urinary CPR levels were 989 mg/dL (54.9 mmol/L), 0.62 ng/mL, and 13.4 μg/d, respectively. No islet-related autoantibodies were detected. Therefore, she was diagnosed with TAC-induced DKA. INTERVENTION Intravenous continuous insulin infusion and rapid saline infusion were administered. TAC was discontinued because of its diabetogenic potential. OUTCOMES Sixteen weeks after cessation of TAC administration, she showed good glycemic control without administration of insulin or any oral hypoglycemic agents; her serum CPR level also improved dramatically. These findings suggested that TAC-induced pancreatic beta cell toxicity is reversible. LESSONS We reported a case of TAC-induced DKA with subsequent recovery of pancreatic beta cell function after cessation of TAC, resulting in good glycemic control. As TAC is widely used, we should pay attention to patients' glucose levels even though the TAC concentrations used are within the target range. Furthermore, dose reduction or cessation of TAC should be considered if hyperglycemia is detected during administration of this agent.
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Beyond type 2 diabetes: sodium glucose co-transporter-inhibition in type 1 diabetes.
Biester, T, Kordonouri, O, Danne, T
Diabetes, obesity & metabolism. 2019;:53-61
Abstract
Use of sodium glucose cotransporter (SGLT) inhibitors are a well-established therapeutic option in type 2 diabetes (T2D) with a variety of proven therapeutic benefits. They have become a pillar of current treatment guidelines. In type 1 diabetes (T1D), initial exploratory studies have shown benefits in glycemic control, weight control, and cardiovascular risk parameters, leading to trials aiming for regulatory submission with several agents. Results from four 1-year trials, which included a total of 3052 patients, are now available, demonstrating promising findings that target the unmet needs of patients with T1D with a novel insulin-independent adjunct therapy. However, these positive effects must be balanced against the risks associated with this class of drugs. Specifically, current T1D studies have shown an increased risk of diabetic ketoacidosis (DKA), which, in some cases, presented with only slightly elevated glucose levels. While this complication may be clinically manageable once detected, the metabolic shift towards ketogenesis associated with this class of agents mandates appropriate patient selection. Currently, there are no validated tools for DKA risk assessment. Although the experience gained in studies and off-label use provides some indication for appropriate patient selection, this would have to be evaluated closely in the event that these drugs would receive regulatory approval. Risk mitigation includes training in ketone measurement (preferably as blood β-hydroxybutyrate testing), teaching the concept of euglycemic DKA, and providing a clear treatment algorithm to avoid progression of ketosis to full-blown DKA. Because similar unmet needs also exist in pediatric population studies, risk mitigation in youth should be initiated as well to allow an evidence-based, risk-benefit assessment in this vulnerable population.
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Ketoacidosis Due to Empagliflozin, a Paradigm Shift: Case Report and Review of Literature.
Hernandez-Quiles, C, Ramirez-Duque, N, Acosta-Delgado, D
Current diabetes reviews. 2019;(4):259-262
Abstract
INTRODUCTION Sodium-glucose cotransporter 2(SGLT2)-inhibitors are new antihyperglycemic agents that have shown a reduction in cardiovascular events in type 2 diabetes mellitus. Recent warnings have been developed about an increased risk of euglycemic and moderate hyperglycemic diabetic ketoacidosis with the use of SGLT2 inhibitors, but its real incidence is not available yet. CASE REPORT We present a case of DKA with moderate hyperglycemia in a patient treated with metformin and empagliflozin. CONCLUSION DKA in patients treated with SGLT2 inhibitors can be presented as euglycemic and moderated hyperglycemia. This special presentation poses a physician's challenge.